Loss of FOCAD, operating via the SKI messenger RNA surveillance pathway, causes a pediatric syndrome with liver cirrhosis

Ricardo Moreno Traspas; Tze Shin Teoh; Pui-Mun Wong; Michael Maier; Crystal Y Chia; Kenneth Lay; Nur Ain Ali; Austin Larson; Fuad Al Mutairi; Nouriya Abbas Al-Sannaa; Eissa Ali Faqeih; Majid Alfadhel; Huma Arshad Cheema; Juliette Dupont; Stéphane Bézieau; Bertrand Isidor; Dorrain Yanwen Low; Yulan Wang; Grace Tan; Poh San Lai; Hugues Piloquet; Madeleine Joubert; Hulya Kayserili; Kimberly A Kripps; Shareef A Nahas; Eric P Wartchow; Mikako Warren; Gandham SriLakshmi Bhavani; Majed Dasouki; Renata Sandoval; Elisa Carvalho; Luiza Ramos; Gilda Porta; Bin Wu; Harsha Prasada Lashkari; Badr AlSaleem; Raeda M BaAbbad; Anabela Natália Abreu Ferrão; Vasiliki Karageorgou; Natalia Ordonez-Herrera; Suliman Khan; Peter Bauer; Benjamin Cogne; Aida M Bertoli-Avella; Marie Vincent; Katta Mohan Girisha

doi:10.1038/s41588-022-01120-0

Loss of FOCAD, operating via the SKI messenger RNA surveillance pathway, causes a pediatric syndrome with liver cirrhosis

Ricardo Moreno Traspas, Tze Shin Teoh, Pui-Mun Wong, Michael Maier, Crystal Y Chia, Kenneth Lay, Nur Ain Ali, Austin Larson, Fuad Al Mutairi, Nouriya Abbas Al-Sannaa, Eissa Ali Faqeih, Majid Alfadhel, Huma Arshad Cheema, Juliette Dupont, Stéphane Bézieau, Bertrand Isidor, Dorrain Yanwen Low, Yulan Wang, Grace Tan, Poh San LaiHugues Piloquet, Madeleine Joubert, Hulya Kayserili, Kimberly A Kripps, Shareef A Nahas, Eric P Wartchow, Mikako Warren, Gandham SriLakshmi Bhavani, Majed Dasouki, Renata Sandoval, Elisa Carvalho, Luiza Ramos, Gilda Porta, Bin Wu, Harsha Prasada Lashkari, Badr AlSaleem, Raeda M BaAbbad, Anabela Natália Abreu Ferrão, Vasiliki Karageorgou, Natalia Ordonez-Herrera, Suliman Khan, Peter Bauer, Benjamin Cogne, Aida M Bertoli-Avella, Marie Vincent, Katta Mohan Girisha

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

Abstract

Cirrhosis is usually a late-onset and life-threatening disease characterized by fibrotic scarring and inflammation that disrupts liver architecture and function. While it is typically the result of alcoholism or hepatitis viral infection in adults, its etiology in infants is much less understood. In this study, we report 14 children from ten unrelated families presenting with a syndromic form of pediatric liver cirrhosis. By genome/exome sequencing, we found recessive variants in FOCAD segregating with the disease. Zebrafish lacking focad phenocopied the human disease, revealing a signature of altered messenger RNA (mRNA) degradation processes in the liver. Using patient's primary cells and CRISPR-Cas9-mediated inactivation in human hepatic cell lines, we found that FOCAD deficiency compromises the SKI mRNA surveillance pathway by reducing the levels of the RNA helicase SKIC2 and its cofactor SKIC3. FOCAD knockout hepatocytes exhibited lowered albumin expression and signs of persistent injury accompanied by CCL2 overproduction. Our results reveal the importance of FOCAD in maintaining liver homeostasis and disclose a possible therapeutic intervention point via inhibition of the CCL2/CCR2 signaling axis.

Original language	English (US)
Pages (from-to)	1214-1226
Number of pages	13
Journal	Nature Genetics
Volume	54
Issue number	8
DOIs	https://doi.org/10.1038/s41588-022-01120-0
State	Published - Jul 21 2022
Externally published	Yes

Bibliographical note

KAUST Repository Item: Exported on 2022-12-12
Acknowledgements: We are grateful to the families of affected individuals for their participation and kind cooperation in this study. We are also grateful to all members of the Reversade laboratory for constructive discussions and suggestions. We thank R. Weber (Hannover Medical School, Germany) for providing the FOCAD expression construct used for our transient transfections, as well as A. van Hoof (University of Texas Health Science Center at Houston, Texas, USA) and J. Mendell (University of Texas Southwestern Medical Center, Texas, USA) for their insights on the biology of the SKI complex. M.M. was supported by a Career Development Award (CDF Project NR C210812055) from the A*STAR, Biomedical Research Council (Singapore). K.M.G. was supported by the Clinical Research Center grant (IA/CRC/20/1/600002) from India Alliance (India). The authors also thank the King Fahad Medical City Research Center (Saudi Arabia) for the partial support to E.A.F. (grant no. 019-052). B.R. is a fellow of the Branco Weiss Foundation (Switzerland) and the National Research Foundation (Singapore), and an A*STAR and EMBO Young Investigator. This work was also supported by an inaugural Use-Inspired Basic Research (UIBR) central fund and a Brain-Body Initiative (BBI) grant in Neurometabolism to B.R. from the Agency for Science, Technology and Research (A*STAR) in Singapore.

ASJC Scopus subject areas

Genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41588-022-01120-0

https://repository.kaust.edu.sa/bitstream/10754/679809/1/R.%20M.%20Traspas%20et%20al.%2c%20%282022%29.pdf

Cite this

Moreno Traspas, R., Teoh, T. S., Wong, P.-M., Maier, M., Chia, C. Y., Lay, K., Ali, N. A., Larson, A., Al Mutairi, F., Al-Sannaa, N. A., Faqeih, E. A., Alfadhel, M., Cheema, H. A., Dupont, J., Bézieau, S., Isidor, B., Low, D. Y., Wang, Y., Tan, G., ... Girisha, K. M. (2022). Loss of FOCAD, operating via the SKI messenger RNA surveillance pathway, causes a pediatric syndrome with liver cirrhosis. Nature Genetics, 54(8), 1214-1226. https://doi.org/10.1038/s41588-022-01120-0

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title = "Loss of FOCAD, operating via the SKI messenger RNA surveillance pathway, causes a pediatric syndrome with liver cirrhosis",

abstract = "Cirrhosis is usually a late-onset and life-threatening disease characterized by fibrotic scarring and inflammation that disrupts liver architecture and function. While it is typically the result of alcoholism or hepatitis viral infection in adults, its etiology in infants is much less understood. In this study, we report 14 children from ten unrelated families presenting with a syndromic form of pediatric liver cirrhosis. By genome/exome sequencing, we found recessive variants in FOCAD segregating with the disease. Zebrafish lacking focad phenocopied the human disease, revealing a signature of altered messenger RNA (mRNA) degradation processes in the liver. Using patient's primary cells and CRISPR-Cas9-mediated inactivation in human hepatic cell lines, we found that FOCAD deficiency compromises the SKI mRNA surveillance pathway by reducing the levels of the RNA helicase SKIC2 and its cofactor SKIC3. FOCAD knockout hepatocytes exhibited lowered albumin expression and signs of persistent injury accompanied by CCL2 overproduction. Our results reveal the importance of FOCAD in maintaining liver homeostasis and disclose a possible therapeutic intervention point via inhibition of the CCL2/CCR2 signaling axis.",

author = "{Moreno Traspas}, Ricardo and Teoh, {Tze Shin} and Pui-Mun Wong and Michael Maier and Chia, {Crystal Y} and Kenneth Lay and Ali, {Nur Ain} and Austin Larson and {Al Mutairi}, Fuad and Al-Sannaa, {Nouriya Abbas} and Faqeih, {Eissa Ali} and Majid Alfadhel and Cheema, {Huma Arshad} and Juliette Dupont and St{\'e}phane B{\'e}zieau and Bertrand Isidor and Low, {Dorrain Yanwen} and Yulan Wang and Grace Tan and Lai, {Poh San} and Hugues Piloquet and Madeleine Joubert and Hulya Kayserili and Kripps, {Kimberly A} and Nahas, {Shareef A} and Wartchow, {Eric P} and Mikako Warren and Bhavani, {Gandham SriLakshmi} and Majed Dasouki and Renata Sandoval and Elisa Carvalho and Luiza Ramos and Gilda Porta and Bin Wu and Lashkari, {Harsha Prasada} and Badr AlSaleem and BaAbbad, {Raeda M} and {Abreu Ferr{\~a}o}, {Anabela Nat{\'a}lia} and Vasiliki Karageorgou and Natalia Ordonez-Herrera and Suliman Khan and Peter Bauer and Benjamin Cogne and Bertoli-Avella, {Aida M} and Marie Vincent and Girisha, {Katta Mohan}",

note = "KAUST Repository Item: Exported on 2022-12-12 Acknowledgements: We are grateful to the families of affected individuals for their participation and kind cooperation in this study. We are also grateful to all members of the Reversade laboratory for constructive discussions and suggestions. We thank R. Weber (Hannover Medical School, Germany) for providing the FOCAD expression construct used for our transient transfections, as well as A. van Hoof (University of Texas Health Science Center at Houston, Texas, USA) and J. Mendell (University of Texas Southwestern Medical Center, Texas, USA) for their insights on the biology of the SKI complex. M.M. was supported by a Career Development Award (CDF Project NR C210812055) from the A*STAR, Biomedical Research Council (Singapore). K.M.G. was supported by the Clinical Research Center grant (IA/CRC/20/1/600002) from India Alliance (India). The authors also thank the King Fahad Medical City Research Center (Saudi Arabia) for the partial support to E.A.F. (grant no. 019-052). B.R. is a fellow of the Branco Weiss Foundation (Switzerland) and the National Research Foundation (Singapore), and an A*STAR and EMBO Young Investigator. This work was also supported by an inaugural Use-Inspired Basic Research (UIBR) central fund and a Brain-Body Initiative (BBI) grant in Neurometabolism to B.R. from the Agency for Science, Technology and Research (A*STAR) in Singapore.",

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month = jul,

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doi = "10.1038/s41588-022-01120-0",

language = "English (US)",

volume = "54",

pages = "1214--1226",

journal = "Nature Genetics",

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number = "8",

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Moreno Traspas, R, Teoh, TS, Wong, P-M, Maier, M, Chia, CY, Lay, K, Ali, NA, Larson, A, Al Mutairi, F, Al-Sannaa, NA, Faqeih, EA, Alfadhel, M, Cheema, HA, Dupont, J, Bézieau, S, Isidor, B, Low, DY, Wang, Y, Tan, G, Lai, PS, Piloquet, H, Joubert, M, Kayserili, H, Kripps, KA, Nahas, SA, Wartchow, EP, Warren, M, Bhavani, GS, Dasouki, M, Sandoval, R, Carvalho, E, Ramos, L, Porta, G, Wu, B, Lashkari, HP, AlSaleem, B, BaAbbad, RM, Abreu Ferrão, AN, Karageorgou, V, Ordonez-Herrera, N, Khan, S, Bauer, P, Cogne, B, Bertoli-Avella, AM, Vincent, M & Girisha, KM 2022, 'Loss of FOCAD, operating via the SKI messenger RNA surveillance pathway, causes a pediatric syndrome with liver cirrhosis', Nature Genetics, vol. 54, no. 8, pp. 1214-1226. https://doi.org/10.1038/s41588-022-01120-0

TY - JOUR

T1 - Loss of FOCAD, operating via the SKI messenger RNA surveillance pathway, causes a pediatric syndrome with liver cirrhosis

AU - Moreno Traspas, Ricardo

AU - Teoh, Tze Shin

AU - Wong, Pui-Mun

AU - Maier, Michael

AU - Chia, Crystal Y

AU - Lay, Kenneth

AU - Ali, Nur Ain

AU - Larson, Austin

AU - Al Mutairi, Fuad

AU - Al-Sannaa, Nouriya Abbas

AU - Faqeih, Eissa Ali

AU - Alfadhel, Majid

AU - Cheema, Huma Arshad

AU - Dupont, Juliette

AU - Bézieau, Stéphane

AU - Isidor, Bertrand

AU - Low, Dorrain Yanwen

AU - Wang, Yulan

AU - Tan, Grace

AU - Lai, Poh San

AU - Piloquet, Hugues

AU - Joubert, Madeleine

AU - Kayserili, Hulya

AU - Kripps, Kimberly A

AU - Nahas, Shareef A

AU - Wartchow, Eric P

AU - Warren, Mikako

AU - Bhavani, Gandham SriLakshmi

AU - Dasouki, Majed

AU - Sandoval, Renata

AU - Carvalho, Elisa

AU - Ramos, Luiza

AU - Porta, Gilda

AU - Wu, Bin

AU - Lashkari, Harsha Prasada

AU - AlSaleem, Badr

AU - BaAbbad, Raeda M

AU - Abreu Ferrão, Anabela Natália

AU - Karageorgou, Vasiliki

AU - Ordonez-Herrera, Natalia

AU - Khan, Suliman

AU - Bauer, Peter

AU - Cogne, Benjamin

AU - Bertoli-Avella, Aida M

AU - Vincent, Marie

AU - Girisha, Katta Mohan

N1 - KAUST Repository Item: Exported on 2022-12-12 Acknowledgements: We are grateful to the families of affected individuals for their participation and kind cooperation in this study. We are also grateful to all members of the Reversade laboratory for constructive discussions and suggestions. We thank R. Weber (Hannover Medical School, Germany) for providing the FOCAD expression construct used for our transient transfections, as well as A. van Hoof (University of Texas Health Science Center at Houston, Texas, USA) and J. Mendell (University of Texas Southwestern Medical Center, Texas, USA) for their insights on the biology of the SKI complex. M.M. was supported by a Career Development Award (CDF Project NR C210812055) from the A*STAR, Biomedical Research Council (Singapore). K.M.G. was supported by the Clinical Research Center grant (IA/CRC/20/1/600002) from India Alliance (India). The authors also thank the King Fahad Medical City Research Center (Saudi Arabia) for the partial support to E.A.F. (grant no. 019-052). B.R. is a fellow of the Branco Weiss Foundation (Switzerland) and the National Research Foundation (Singapore), and an A*STAR and EMBO Young Investigator. This work was also supported by an inaugural Use-Inspired Basic Research (UIBR) central fund and a Brain-Body Initiative (BBI) grant in Neurometabolism to B.R. from the Agency for Science, Technology and Research (A*STAR) in Singapore.

PY - 2022/7/21

Y1 - 2022/7/21

N2 - Cirrhosis is usually a late-onset and life-threatening disease characterized by fibrotic scarring and inflammation that disrupts liver architecture and function. While it is typically the result of alcoholism or hepatitis viral infection in adults, its etiology in infants is much less understood. In this study, we report 14 children from ten unrelated families presenting with a syndromic form of pediatric liver cirrhosis. By genome/exome sequencing, we found recessive variants in FOCAD segregating with the disease. Zebrafish lacking focad phenocopied the human disease, revealing a signature of altered messenger RNA (mRNA) degradation processes in the liver. Using patient's primary cells and CRISPR-Cas9-mediated inactivation in human hepatic cell lines, we found that FOCAD deficiency compromises the SKI mRNA surveillance pathway by reducing the levels of the RNA helicase SKIC2 and its cofactor SKIC3. FOCAD knockout hepatocytes exhibited lowered albumin expression and signs of persistent injury accompanied by CCL2 overproduction. Our results reveal the importance of FOCAD in maintaining liver homeostasis and disclose a possible therapeutic intervention point via inhibition of the CCL2/CCR2 signaling axis.

AB - Cirrhosis is usually a late-onset and life-threatening disease characterized by fibrotic scarring and inflammation that disrupts liver architecture and function. While it is typically the result of alcoholism or hepatitis viral infection in adults, its etiology in infants is much less understood. In this study, we report 14 children from ten unrelated families presenting with a syndromic form of pediatric liver cirrhosis. By genome/exome sequencing, we found recessive variants in FOCAD segregating with the disease. Zebrafish lacking focad phenocopied the human disease, revealing a signature of altered messenger RNA (mRNA) degradation processes in the liver. Using patient's primary cells and CRISPR-Cas9-mediated inactivation in human hepatic cell lines, we found that FOCAD deficiency compromises the SKI mRNA surveillance pathway by reducing the levels of the RNA helicase SKIC2 and its cofactor SKIC3. FOCAD knockout hepatocytes exhibited lowered albumin expression and signs of persistent injury accompanied by CCL2 overproduction. Our results reveal the importance of FOCAD in maintaining liver homeostasis and disclose a possible therapeutic intervention point via inhibition of the CCL2/CCR2 signaling axis.

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UR - https://www.nature.com/articles/s41588-022-01120-0

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U2 - 10.1038/s41588-022-01120-0

DO - 10.1038/s41588-022-01120-0

M3 - Article

C2 - 35864190

SN - 1061-4036

VL - 54

SP - 1214

EP - 1226

JO - Nature Genetics

JF - Nature Genetics

IS - 8

ER -

Loss of FOCAD, operating via the SKI messenger RNA surveillance pathway, causes a pediatric syndrome with liver cirrhosis

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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